Anesthesia induces unconsciousness by changing the function of proteins that reside on the surface of a thin membrane that forms a barrier around all cells, according to new research from Weill Cornell Medicine scientists. The findings challenge a century-old concept of how anesthetics work and may help guide the development of new agents associated with fewer side effects.
One of the most important use cases of ontologies is the calculation of similarity scores between a query and items annotated with classes of an ontology. The hierarchical structure of an ontology does not necessarily reflect all relevant aspects of the domain it is modelling, and this can reduce the performance of ontology-based search algorithms. For instance, the classes of phenotype ontologies may be arranged according to anatomical criteria, but individual phenotypic features may affect anatomic entities in opposite ways. Thus, "opposite" classes may be located in close proximity in an ontology; for example enlarged liver and small liver are grouped under abnormal liver size. Using standard similarity measures, these would be scored as being similar, despite in fact being opposites. In this paper, we use information about opposite ontology classes to extend two large phenotype ontologies, the human and the mammalian phenotype ontology. We also show that this information can be used to improve rankings based on similarity measures that incorporate this information. In particular, cosine similarity based measures show large improvements. We hypothesize this is due to the natural embedding of opposite phenotypes in vector space. We support the idea that the expressivity of semantic web technologies should be explored more extensively in biomedical ontologies and that similarity measures should be extended to incorporate more than the pure graph structure defined by the subclass or part-of relationships of the underlying ontologies.
@lpachter Your cup of tea over at UCLA next week? Regulatory & Epigenetic Stochasticity in Development & Disease http://www.ipam.ucla.edu/programs/workshops/regulatory-and-epigenetic-stochasticity-in-development-and-disease
Pachter, a computational biologist, returns to CalTech to study the role and function of RNA.
Pachter, a computational biologist and Caltech alumnus, returns to the Institute to study the role and function of RNA.
Lior Pachter (BS ’94) is Caltech’s new Bren Professor of Computational Biology. Recently, he was elected a fellow of the International Society for Computational Biology, one of the highest honors in the field. We sat down with him to discuss the emerging field of applying computational methods to biology problems, the transition from mathematics to biology, and his return to Pasadena. Continue reading “👓 A Conversation with @LPachter (BS ’94) | Caltech”
The interplay between structural connections and emerging information flow in the human brain remains an open research problem. A recent study observed global patterns of directional information flow in empirical data using the measure of transfer entropy. For higher frequency bands, the overall direction of information flow was from posterior to anterior regions whereas an anterior-to-posterior pattern was observed in lower frequency bands. In this study, we applied a simple Susceptible-Infected-Susceptible (SIS) epidemic spreading model on the human connectome with the aim to reveal the topological properties of the structural network that give rise to these global patterns. We found that direct structural connections induced higher transfer entropy between two brain regions and that transfer entropy decreased with increasing distance between nodes (in terms of hops in the structural network). Applying the SIS model, we were able to confirm the empirically observed opposite information flow patterns and posterior hubs in the structural network seem to play a dominant role in the network dynamics. For small time scales, when these hubs acted as strong receivers of information, the global pattern of information flow was in the posterior-to-anterior direction and in the opposite direction when they were strong senders. Our analysis suggests that these global patterns of directional information flow are the result of an unequal spatial distribution of the structural degree between posterior and anterior regions and their directions seem to be linked to different time scales of the spreading process.
Epigenetics refers to information transmitted during cell division other than the DNA sequence per se, and it is the language that distinguishes stem cells from somatic cells, one organ from another, and even identical twins from each other. In contrast to the DNA sequence, the epigenome is relatively susceptible to modification by the environment as well as stochastic perturbations over time, adding to phenotypic diversity in the population. Despite its strong ties to the environment, epigenetics has never been well reconciled to evolutionary thinking, and in fact there is now strong evidence against the transmission of so-called “epi-alleles,” i.e. epigenetic modifications that pass through the germline.
However, genetic variants that regulate stochastic fluctuation of gene expression and phenotypes in the offspring appear to be transmitted as an epigenetic or even Lamarckian trait. Furthermore, even the normal process of cellular differentiation from a single cell to a complex organism is not understood well from a mathematical point of view. There is increasingly strong evidence that stem cells are highly heterogeneous and in fact stochasticity is necessary for pluripotency. This process appears to be tightly regulated through the epigenome in development. Moreover, in these biological contexts, “stochasticity” is hardly synonymous with “noise”, which often refers to variation which obscures a “true signal” (e.g., measurement error) or which is structural, as in physics (e.g., quantum noise). In contrast, “stochastic regulation” refers to purposeful, programmed variation; the fluctuations are random but there is no true signal to mask.
This workshop will serve as a forum for scientists and engineers with an interest in computational biology to explore the role of stochasticity in regulation, development and evolution, and its epigenetic basis. Just as thinking about stochasticity was transformative in physics and in some areas of biology, it promises to fundamentally transform modern genetics and help to explain phase transitions such as differentiation and cancer.
This workshop will include a poster session; a request for poster titles will be sent to registered participants in advance of the workshop.
Adam Arkin (Lawrence Berkeley Laboratory)
Gábor Balázsi (SUNY Stony Brook)
Domitilla Del Vecchio (Massachusetts Institute of Technology)
Michael Elowitz (California Institute of Technology)
Andrew Feinberg (Johns Hopkins University)
Don Geman (Johns Hopkins University)
Anita Göndör (Karolinska Institutet)
John Goutsias (Johns Hopkins University)
Garrett Jenkinson (Johns Hopkins University)
Andre Levchenko (Yale University)
Olgica Milenkovic (University of Illinois)
Johan Paulsson (Harvard University)
Leor Weinberger (University of California, San Francisco (UCSF))
Whether by virtue of being prepared in a slowly relaxing, high-free energy initial condition, or because they are constantly dissipating energy absorbed from a strong external drive, many systems subject to thermal fluctuations are not expected to behave in the way they would at thermal equilibrium. Rather, the probability of finding such a system in a given microscopic arrangement may deviate strongly from the Boltzmann distribution, raising the question of whether thermodynamics still has anything to tell us about which arrangements are the most likely to be observed. In this work, we build on past results governing nonequilibrium thermodynamics and define a generalized Helmholtz free energy that exactly delineates the various factors that quantitatively contribute to the relative probabilities of different outcomes in far-from-equilibrium stochastic dynamics. By applying this expression to the analysis of two examples—namely, a particle hopping in an oscillating energy landscape and a population composed of two types of exponentially growing self-replicators—we illustrate a simple relationship between outcome-likelihood and dissipative history. In closing, we discuss the possible relevance of such a thermodynamic principle for our understanding of self-organization in complex systems, paying particular attention to a possible analogy to the way evolutionary adaptations emerge in living things.
Notions like meaning, signal, intentionality, are difficult to relate to a physical word. I study a purely physical definition of "meaningful information", from which these notions can be derived. It is inspired by a model recently illustrated by Kolchinsky and Wolpert, and improves on Dretske classic work on the relation between knowledge and information. I discuss what makes a physical process into a "signal".
Understanding the emergence and robustness of life requires accounting for both chemical specificity and statistical generality. We argue that the reverse of a common observation—that life requires a source of free energy to persist—provides an appropriate principle to understand the emergence, organization, and persistence of life on earth. Life, and in particular core biochemistry, has many properties of a relaxation channel that was driven into existence by free energy stresses from the earth's geochemistry. Like lightning or convective storms, the carbon, nitrogen, and phosphorus fluxes through core anabolic pathways make sense as the order parameters in a phase transition from an abiotic to a living state of the geosphere. Interpreting core pathways as order parameters would both explain their stability over billions of years, and perhaps predict the uniqueness of specific optimal chemical pathways.
Driven by technological progress, human life expectancy has increased greatly since the nineteenth century. Demographic evidence has revealed an ongoing reduction in old-age mortality and a rise of the maximum age at death, which may gradually extend human longevity. Together with observations that lifespan in various animal species is flexible and can be increased by genetic or pharmaceutical intervention, these results have led to suggestions that longevity may not be subject to strict, species-specific genetic constraints. Here, by analysing global demographic data, we show that improvements in survival with age tend to decline after age 100, and that the age at death of the world’s oldest person has not increased since the 1990s. Our results strongly suggest that the maximum lifespan of humans is fixed and subject to natural constraints.
Almost 40 years ago, Leonard Hayflick discovered that cultured normal human cells have limited capacity to divide, after which they become senescent — a phenomenon now known as the ‘Hayflick limit’. Hayflick's findings were strongly challenged at the time, and continue to be questioned in a few circles, but his achievements have enabled others to make considerable progress towards understanding and manipulating the molecular mechanisms of ageing.
Biomolecular systems like molecular motors or pumps, transcription and translation machinery, and other enzymatic reactions, can be described as Markov processes on a suitable network. We show quite generally that, in a steady state, the dispersion of observables, like the number of consumed or produced molecules or the number of steps of a motor, is constrained by the thermodynamic cost of generating it. An uncertainty ε requires at least a cost of 2k_B T/ε^2 independent of the time required to generate the output.
Recent advances in fields ranging from cosmology to computer science have hinted at a possible deep connection between intelligence and entropy maximization, but no formal physical relationship between them has yet been established. Here, we explicitly propose a first step toward such a relationship in the form of a causal generalization of entropic forces that we find can cause two defining behaviors of the human “cognitive niche”—tool use and social cooperation—to spontaneously emerge in simple physical systems. Our results suggest a potentially general thermodynamic model of adaptive behavior as a nonequilibrium process in open systems.
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Life was long thought to obey its own set of rules. But as simple systems show signs of lifelike behavior, scientists are arguing about whether this apparent complexity is all a consequence of thermodynamics.
This is a nice little general interest article by Philip Ball that does a relatively good job of covering several of my favorite topics (information theory, biology, complexity) for the layperson. While it stays relatively basic, it links to a handful of really great references, many of which I’ve already read, though several appear to be new to me. 
While Ball has a broad area of interests and coverage in his work, he’s certainly one of the best journalists working in this subarea of interests today. I highly recommend his work to those who find this area interesting.
Scientists are uncovering how our bodies — and everything within them — tell right from left.